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1 INTRO 1. Definitions a. Endocrine – hormones move through blood to act on specific R on distant cells b. Paracrine – hormones act on adjacent cells c. Autocrine – hormones act on the secreting cell d. Neurocrine – neural cells release hormones into the blood 2. Chemical classification a. Amino-acid derivatives: catecholamines, thyroid hormones b. Simple polypeptides: releasing hormones/factors of hypothalamus, ACTH, PTH, GH, PRL, AVP, insulin, glucagon c. Complex polypeptides (e.g. modified by glycosylation): LH, FSH, TSH, hCG d. Lipids: steroid hormones (cortisol, aldosterone), sex hormones (testosterone, estradiol, progesterone), Vit D 3. Physical classification a. Hydrophilic: bind to cell surface receptors i. Catecholamines, all simple + complex polypeptides b. Hydrophobic: bind to receptors in cytoplasm, then transport/action on nucleus i. All lipids + thyroid hormones 4. Conversions a. All polypeptide hormones are synthesized as pre-hormones (have signal peptide that target for secretion, removed later) i. Insulin + PTH exist as pre-pro-hormones (have extra piece in addition to signal peptide, both removed for activity) b. Many converted at target cell (ex) cortisol cortisone (inactive) by mineralocorticoid cells, essentially prevents Cushings 5. Regulation via secretion (circadian, negative fb), metabolism (degraded, activated), and at target cells (amplified, downregulated) 6. MOA: hormone binding conformation change in R 2nd messenger ↑↓rate of txn of target genes a. G-protein R: 7x transmembrane spanning amino acid chain w/ alpha (GTPase), beta, gamma subunits i. Gs-adenylate cyclase: converts ATP cAMP, which activates pkA pCREB 1. Pseudo-hypo-parathyroidism caused by Gs mutation, hypoCa w/ normal or high PTH (PTH resistance), and Albright hereditary osteodystrophy (short/moon face/short 4th metacarpal) ii. Gq-PLC: converts PIP2 P3 + DAG, which activates pkC pAP1 b. Tyrosine kinase R: autoP of R c. Intracellular R: H-R complex acts as TF, thus directly binds promoter 7. Measurement a. Can be affected by food/EtOH, time of day (ex) cortisol high in am, low in pm, whether hormone is free/bound i. RIA: tracer is labeled hormone, std curve using known [ ]s unlabeled hormone w/ constant tracer, compare pt to curve ii. IRMA (immunoradiometric): hormone is sandwiched btw 2 Ab (one immobilized on bead, other w/ tag for detection) iii. Dynamic testing: 1. failed suppression = autonomy/overactivity (ex) Cushings 2. failed stimulation = defc’y HYPOTHALAMIC-PITUITARY AXIS 1. Hypothalamus a. Maintains homeostasis by initiating hormonal compensatory changes, link btw CNS and pituitary fx b. Small paraventricular neurons release hormones into hypophyseal portal system, which supplies anterior pituitary c. Large magnocellular neurons of supraoptic and periventricular nuclei send axons to post pit that release ADH/oxytocin 2. Sella a. anatomic location of pituitary, bordered by cavernous sinuses b. 1 – int carotid, 2 – CN III, 3 – CN IV, 6 – CN VI 3. Pituitary a. Anterior (adenohypophysis) = pars distalis, pars tuberalis i. Glandular epithelium w/ nests of cells in capillary network 1. Acidophils: somatotrophs, lactotrophs (aka mammotrophs) 2. Basophils: thyrotrophs, corticotrophs, gonadotrophs ii. Folliculostellate cells are supporting cells; null cells are reserve cells; oncocytes ↑ w/ age iii. Hormones: GH, TSH, ACTH, LH, FSH, PRL HYPOTHALAMUS TRH CRH GnRH GHRH SRIF (somatostatin) PIF (dopamine) b. 4. ANT PITUITARY secretion TSH, PRL secretion ACTH secretion LH, FSH secretion GH (-) of GH release tonic (-) of PRL release PERIPHERAL TARGET secretion thyroid hormone secretion cortisol secretion gonadal steroids, stimulates follicular devel’p/spermatogenesis IGF-1 production (neg fb), ↑ protein synth, ↑ overall growth → opposite of GHRH PRL lactation, inhibition of GnRH/LH/FSH Posterior (neurohypophysis) = pars nervosa, infundibular stalk, median eminence iv. Neuroectroderm w/ hypothalamic axons containing secretory granules of hormone (Herring bodies) v. Pituicytes are supporting cells (modified glial cells); assoc w/ pituicytoma and granular cell tumor vi. Hormones: oxytocin, ADH (inappropriate ADH release leads to diabetes insipidus) Pituitary adenomas (most common pituitary tumor) a. Most are sporadic monoclonal tumors but MEN-1 and McCune-Albright predispose to adenoma formation b. Micro <1cm vs macro >1cm, visualize via MRI c. Most are prolactinomas, i.e. fxn’al tumors that secrete excess PRL (see hyperpit table) i. In females, tend to be microadenomas w/ moderate PRL elevation oligo/amenorrhea (b/c PRL (-) GnRH) ii. In males, tend to be macroadenomas w/ severe PRL elevation impotence iii. Other sx: HA, bitemporal hemianopsia (if presses on optic chiasm), CN III/IV/VI palsy (if grows into cavernous sinus) iv. Dx: morning blood draw of all major pituitary hormones v. Tx: dopamine agonist (ex) bromocriptine/cabergoline d. Non-fxn’al tumors most commonly gonadotrophal (have hormones but can’t secrete) normal levels of hormone + mass effect e. Also invasive (usually ACTH secreting), atypical (↑ proliferation, ↑p53), carcinoma (very rare) 2 5. 6. 7. Other sellar tumors a. Craniopharyngioma: remnant of Rathke’s pouch, benign, common in children, HA/hypopit/diabetes insipidus, “motor oil” cyst i. Tx via surgical excision (locally invasive); high recurrence rate, squamous epithelium b. Chordoma: malignant tumor derived from notochord, common in young adults, HA/CN III palsy, vacuolated cells (physaliphorous) Non-neoplastic lesions a. Pituitary hyperplasia: response to HMS RHs, diffuse vs nodular, ectopic (due to tumor) vs orthotopic (due to end-organ failure) i. (ex) Prolactin cell hyperplasia: physiologic w/ pregnancy, pathologic if assoc w/ other dz like Cushings, hypothyroidism b. Also lymphocytic hypophysitis, sarcoidosis (see pituitary syndromes table) Hypopituitarism a. Insufficent GH in adults: osteoporosis, abnormal fat/lean muscle ratio, low self-esteem, tx aims to normalize IGF-1 levels i. Tx adult GH defc’y w/ nightly GH injections (S/E: edema, arthralgias, ↓ glucose tolerance) b. Genetic defects Dz PATHOPHYSIOLOGY Kallman’s Syndrome Insufficient GnRH Aberrant GnRH cell migration no GnRH control of ant pit (HMS hypogonadism) Congenital hormone defc’y Isolated GH defc’y PROP-1 mutation no Pit-1 txn factor no somato, lacto, thryotrophs Defect in GHRH secretion c. Tissue resistance GH resistance (Laron dwarfs) GH R abnormality IGF-1 defc’y w/ hi GH Androgen insensitivity syndrome AR mutation (X-linked) 8. Hyperpituitarism Hyperprolactinemia (normal is ˂ 29ng/mL) Acromegaly (Gigantism if pre-pubertal) Cushings dz Decelerated growth ~2yoa Childhood: short stature, small fingers/toes Tx with IGF-1 Geno XY, pheno female w/amenorrhea ↑ estrogens (commonly from pregnancy) ↑ TRH (1˚ hypothyroidism) Drugs (dopamine antagonists like TCAs/neuroleptics) Prolactinomas Infundibular stalk compression (loss of (-) by dopa) Galactorrhea, amenorrhea + if tumor, sx listed above Tx: dopamine agonist (bromocriptine) Excessive GH + high IGF-1 (ex) huge pituitary tumor w/ slow growth CHF, colon/breast cancer premature mortality Excessive ACTH from pituitary tumor Early sx: sleep apnea, carpal tunnel syndrome Hyperglossia, enlarged hands/feet/jaw Tx: surgery if small tumor, SRIF, GH antagonist Obesity/HTN/osteoporosis/poor wound heal/DM Dx by O/N dexamethasone suppression test 9. Pituitary syndromes CNS Irradiation Hypothalamus VERY sensitive to radiation 1˚ CSF enters sella compression of pituitary Empty Sella Syndrome 2˚ due to infarction of known tumor Pituitary Apoplexy Hemorrhagic infarction of pituitary or pituitary adenoma – medical emergency Pituitary size naturally ↑ during preg risk for outgrowing Sheehan’s Syndrome blood supply post-partum infarction Mass infiltration by lymphs/plasma cells tissue destruction Lymphocytic hypophysitis Autoimmune Sarcoidosis CLINICAL Anosmia + hypogonadism Anterior pituitary is unharmed Tx with chronic pulsatile GnRH or FSH/LH GH, PRL, TSH defc’y (ACTH and LH/FSH spared) Infiltration diabetes insipidus/1-OHase defc’y hyperCa Common Panpituitary hormone defc’y Obese middle-aged women w/ benign intracranial HTN Usually pituitary fxn is fine Excruciating HA, pt collapses, stiff neck, fever Tx: decompression, corticosteroids for stress Inability to lactate following delivery, menses problems, genital alopecia Mainly occurs during pregnancy Sx of hypopituitarism, pain 12/10 Conservative mgmt (often resolves) but may need chronic replacement of hormones Tx underlying dz w/ high dose steroids Generally involves HMS and stalk 10. Laboratory testing used to differentiate hypothalamic vs pituitary disease a. If hypothalamic d/o then other functions of hypothalamus will be impaired (ex) HR, circadian rhythm b. IV administration of hypothalamic hormones MAY induce a pituitary response i. If pituitary responds = hypothalamic dysfunction ii. If pituitary does not respond = 1. Lack of priming (lack of exposure atrophy of targets) 2. Excessive negative feedback 3. Absence of a specific cell target (mutation, destruction) iii. Acute admin of CRH can help distinguish Cushing’s Dz (ACTH secreting tumor of pituitary) from ectopic ACTH production 1. Ectopic won’t respond, whereas Cushing’s ↑ACTH iv. Chronic GnRH used to tx Kallmann’s Syndrome v. hrTSH used to dx and tx metastatic thyroid cancer (↑ uptake I131 by cancer cells) vi. SRIF used to tx acromegaly (↓ GH and IGF-1) vii. Dx acromegaly via glucose suppression test: failure of GH to ↓ to ˂ 0.8 ng/mL in 1h is diagnostic 1. ITT (insulin tolerance test): dx adult GH deficiency (hypoglycemia should ↑ GH); IGF-1 not good screening test! 3 ADRENAL CORTEX/CORTISOL 1. Steroid biosynthesis from cholesterol (into adrenal via LDL R) a. Zona glomerulosa: mineralocorticoids (aldosterone), req CYP11B2 (11b-OHase) + 21-OHase b. Zona fasciculata: glucocorticoids (cortisol), 17-Hydroxy Steroids, req CYP11B1 (11b-OHase) + 21-OHase c. Zona reticularis: androgens (DHEA, androstenedione), 17-Ketone Steroids, req CYP17 (17a-OHase) i. Androstenedione can be converted to testosterone or estrone (by aromatase) 2. Steroid actions a. Glucocorticoids – metabolism (opposes insulin), immune response/anti-inflamm (stabilize lysosomes), stress response i. Carbohydrates: ↑ blood glucose for GNG via inhibition of insulin ↓glucose uptake ii. Lipids: ↑ lipolysis iii. Proteins: ↑ proteolysis for GNG b. Mineralocorticoids – BP, vascular volume, electrolytes c. Androgens – secondary sex characteristics d. Both gluco/mineralocorticoids can bind mineralo R, ONLY glucocorticoids can bind gluco R, both = intracellular steroid R i. Mineralo R gain specificity by inactivating cortisol (coverts to cortisone) ii. In high [], cortisol can also activate mineralocorticoid receptor aldosterone effects 3. Regulation of ACTH a. Stimulated by CRH, stress, exercise, etc (ACTH itself inhibits CRH in negative fb) b. ↓ by high plasma cortisol (negative fb) c. Influenced by sleep-wake cycle (peak is just before waking, lowest just before sleeping), cortisol levels follow i. Note: random cortisol level does not reflect secretion pattern, because ACTH secretion is pulsatile/diurnal rhythm ii. Note: plasma hormone [ ] = secretory rate/metabolic clearance rate (urine free cortisol used to estimate secretion) d. ACTH binds GPCR that ↑cAMP → ↑ cortisol via ↑LDL Rs, ↑cleavage cholesterol, ↑17-hydroxylation e. Most of cortisol is bound to corticosteroid-binding globulin (transcortin) 4. Cushing’s Syndrome: systemic syndrome resulting from chronic excess cortisol secretion a. Sx: CNS problems (psychosis), excessive salt retention/edema, HTN, impaired glucose tolerance, immunosuppression, stria/ ecchymoses, osteoporosis, wt gain (central obesity, moon-face, fat-pads), alopecia, hirsutism, proximal muscle atrophy b. Etiology i. Exogenous: pharmacologic administration of glucocorticoids (most common) ii. Endogenous 1. ACTH from pituitary tumor aka Cushing’s Disease 2. Ectopic CRH or ACTH, as in from oat-cell carcinoma/medullary thyroid carcinoma a. bilateral adrenal hyperplasia b. Abrupt onset so traditional sx not present - specifically look for hypoK alkalosis and diabetes 3. Cortisol secreting adrenal tumor c. Adrenal function tests i. Indicated if you suspect Cushing’s based on H&P ii. FIRST – screening test, overnight dexamethasone suppression 1. Dexa is 30x more potent than cortisol, thus SHOULD suppress overnight cortisol secretion (via negative fb) LOW plasma cortisol in healthy person 2. Low dose dexa will NOT suppress Cushing’s, so morning plasma cortisol will be elevated iii. SECOND – confirmatory test, low dose dexamethasone suppression 1. If truly Cushings, the dose is still not enough to suppress, and morning plasma cortisol will again be elevated iv. THIRD – establish etiology, plasma ACTH 1. If low, it is an adrenal tumor, if high, it is either Cushings dz or ectopic ACTH tumor v. FOURTH – establish etiology, high dose dexamethasone suppression 1. If cortisol release is suppressed = Cushings dz, as pituitary has R for negative fb control 2. If NOT suppressed, it is an ectopic ACTH secreting tumor, which contains no R vi. CRH test – Cushings pt will have marked ↑ in ACTH in response to CRH (useful, but high dose dexa preferred test) vii. ACTH test (cosyntropin) – normal pt will have ↑ cortisol w/in 1h but may see no ↑ if cortisol already overstimulated 1. Can also distinguish 1° from 2° adrenal insufficiency: both have NO ↑cortisol but 2° has ↑aldosterone viii. Note: 3 tests to distinguish pituitary vs non-pituitary ACTH-secreting tumors: high dose dexa/metyrapone/CRH 1. See hyper-response w/Cushing’s dz (pituitary), no response w/ectopic (non-pituitary) Disease Cushing’s Dz (Pit Tumor) Ectopic ACTH-Secreting Tumor Adrenal Tumor 5. High Dose Dexa Suppression YES NO NO Metyrapone Response CRH Stimulation Plasma ACTH YES NO NO YES NO NO Normal – High High Low Adrenal insufficiency: hypofxn’ing adrenals fail to release sufficient gluco and/or mineralocorticoids a. Primary (problem of adrenal dysfxn) aka Addison’s dz = autoimmune destruction of adrenals i. Both cortisol/aldosterone low + ACTH high b. Secondary (problem of pituitary dysfxn), usually exogenous glucocorticoids (via negative fb) or pituitary damage i. Cortisol low + ACTH low but aldosterone normal (b/c mostly under renin control, not pituitary) c. Sx of primary (Addison’s): hypoNa, hypoTN, hyperK, hyperpigmentation (↑ACTH ↑MSH), vitiligo, fatigue, wt loss, salt craving d. Sx of secondary are similar but NO hyperpigmentation (ACTH not high), NO salt craving (normal aldosterone), and NO hyperK e. Adrenal function tests i. Plasma ACTH: differentiates btw primary/secondary causes ii. ACTH stimulation test: give cortrosyn – if Addison’s, NO response from adrenals 1. With long-standing secondary, there would also be no/low response due to adrenal atrophy iii. Insulin tolerance test: induce hypoglycemia (stressful state), tests whole HPA axis 1. Normally, would see ↑ in cortisol 2. Contraindicated if Addison’s is highly suspected (Addisonian crisis), or hx of CAD, seizure disorder iv. O/N Metyrapone test: inhibits 11β-hydroxylase so 11-deoxycortisol accumulates and ↓cortisol → ↑ ACTH (ACTH test 1st!) 1. ↑↑↑ ACTH w/ Cushing’s dz whereas adrenal tumors/ectopic ACTH syndrome show NO ↑ACTH 4 6. Congenital adrenal hyperplasia: inherited genetic diseases w/ impaired cortisol biosynthesis due to defective enzymes in pathway a. Tx: goal is to ↓ACTH to normal, accomplished via tx w/ cortisol/other glucocorticoids b. 21-hydroxylase deficiency (most common, CYP21A2) i. Blocks formation of gluco/mineralocorticoids low cortisol/aldosterone (aldosterone defc’y is to much lesser extent) ii. Body tries to raise cortisol by ↑ ACTH, but precursors are shunted to androgen pathway female virilization iii. Clinical: virilizing-salt wasting (most severe), virilizing-non salt wasting, adult onset (women only, hirsutism) c. 17-hydroxylase deficiency (CYP17) i. Blocks formation of sex hormones low testosterone ambiguous males ii. Precursors shunted to mineralocortioid pathway HTN, hypoK d. 11-hydroxylase (CYP11B1 or 11-βOHase in z.fasciculata converts 11-deoxycortisol to cortisol) i. Blocks formation of glucocorticoids low cortisol ii. Precursors shunted to mineralocorticoid pathway HTN, hypoK + androgen pathway female virilization e. 11-hydroxylase (CYP11B2 in z.glomerulosa) i. Blocks formation of mineralocorticoids low aldosterone ii. Precursors shunted to glucocorticoid pathway hypoTN, hyperK + androgen pathway female virilization Defective Enzyme 21-OHase 17-OHase 11β-OHase Salt Wasting YES/NO NO NO HTN/HypoK NO YES YES ♀ Virilization YES YES NO Ambiguous ♂ NO NO YES Precocious ♂ YES YES NO Cholesterol 17-OHase Pregnenolone Sex Steroids Progesterone 21-OHase CYP11B2 CYP11B1 Cortisol Aldosterone ENDOCRINE HYPERTENSION/ALDOSTERONE 1. Endocrine HTN: state in which hormonal derangement results in clinically significant HTN a. Suspect if sudden onset in young/old, refractory to 3+ meds, episodic HTN or HTN w/ hypoK b. Specific findings: abdominal bruit in renal HTN, clammy hands/café au lait spot in pheo, central obesity/striae/bruising in Cushings c. All tx aims to control BP while preserving renal fxn TYPE Renal Artery Stenosis (most common) PATHOGENESIS >90% occlusion from AS or fibromuscular dysplasia ischemia activation of RAS ang II release (potent VC) 1° Aldosteronism Hyperaldosterone Na retention + K excretion ↑ intravascular volume (tho NO edema due to aldost escape via ANP release) Neuroendocrine tumor of chromaffin cells (w/in adrenal medulla or extra-adrenal) If ˂ 20y, bilateral→ screen for succinate DH mutation Pheochromocytoma LABS/IMAGING Unilateral, labs normal Bilateral, ↑BUN/creatine (indicate RF) Angiography best (AS looks like beads on string) Metabolic alkalosis ↓ renin, sometimes hypoK High aldosterone:renin Should treat PAC/PRA > 25 CLINICAL Upper flank abdominal bruit Tx ACE (-), aldost R antag, thiazide diuretic Surgery if noncompliant, young, HTN is refractory Salt loading fails to suppress Muscle wasting when K <2.5 Plasma metanephrines if HI risk (hi sensitivity) Urine metanephrines if LO risk (hi specificity) HTN + triad of HA, sweating, palps “10% tumor” Need tx to prevent hi risk of stroke, MI, afib Surgical removal Spironolactone/eplerenone (aldost antag but lots S/E) Surgical removal best Pre-op volume expansion Pre-op /β-blockers Post-op β-blockers HI recurrence rate 5 THYROID/THYROID HORMONE 1. Parafollicular C cells make calcitonin (inhibits osteoclast activity to ↓bone resorption) 2. Follicular cells: produce T3, T4 (T4 peripherally converted to T3, which binds nuclear T3Rs and feeds back on HMS/pit) a. Synth (stimulated by TSH) i. Uptake: I into cell via basilar 2Na/I symporter (need 50 mcg/d intake); Na back out to blood via Na/K ATPase 1. ↑ symporter activity/uptake w/ TSH and ↓uptake w/ large amts iodide or lithium 2. Much of the I taken up is stored as colloid via pendrin transporter (apical) a. Pendred syndrome: pendrin mutation, goiter and congenital deafness ii. Oxidation: I I2 via TPO (thyroid peroxidase) iii. Organification: I2 attaches to tyrosines of TG (thyroglobulin) via TPO iv. Coupling: MITs + DITs T3, T4 via TPO (which is inhibited by PTU(propylthiouracil)/MMI(methimazole)) v. Proteolysis: stored colloid is brought back into cell and T3, T4 is released (inhibited by excess I) b. Transport: 99% bound to TBG, only free hormone is active, T4 in greater [] but T3 more active, converted via 5-monodeiodinase 3. Serum FT4 best in determining thyroid status b/c free levels not affected by other processes (ex) liver dz, OCP. ALWAYS check TSH too! a. Hormone levels naturally drop when sick, pt is still considered euthyroid (sick thyroid syndrome) b. Cancer serum biomarkers: TG for thyroid cancer and calcitonin for medullary cancer DISORDER 1˚ hypothyroidism/Hashimoto 4. 5. 6. 7. FREE T4 LO TSH HI TRH HI Uptake/Scan LO 2˚ hypothyroidism (pit) LO LO HI LO 3˚ hypothyroidism (hypothal) LO LO LO LO 1˚ hyperthyroidism/Graves HI LO LO HI 2˚ hyperthyroidism (pit) HI HI LO HI Iodine deficiency LO HI HI HI Iodine a. Defc’y ↑ TSH compensatory thyroid enlargement + euthyroid OR hypothyroid; cretinism if fetal hypothyroid b. Excess Wolff-Chaikoff effect (transient hypothyroidism) eventual escape w/resumption of normal fxn or hypothyroid c. Excess Jod-Basedow effect: hyperthyroidism due to excess I Goiter: think elderly woman in I deficient area, may be hypo/hyper/euthyroid, tx w/ surgery if sx of compression a. Diffuse: symmetric enlargement vs multi-nodular: asymmetric, heterogenous w/ necrosis, hemorrhage, cysts b. Endemic: nutritional defc’y vs sporadic: idiopathic, enzyme defc’y c. Papillary hyperplasia vs involution of cells d. If impede on recurrent laryngeal n → hoarseness, parathyroids → tetany, stridor, numbness, Chvostek + Trousseau signs Nodules a. Hot = producing hormones so high radio-I uptake, unlikely malignant b. Cold = not producing hormones so low/no radio-I uptake, need biopsy c. Check TSH → if low do uptake scan and if high do biopsy Clinical sx SYSTEM Metabolic Cardiovascular Calorigenic Gastrointestinal Central Nervous Skin & Appendages Musculoskeletal Severe States 8. HYPER Hypermetabolic Amenorrhea ↑ cholesterol metabolism ↑ insulin secretion Wt loss Heat intolerance ↑ HR, SV, CO, PP ↓ PVR Atrial arrhythmias ↑ O2 consumption ↑ appetite ↑ glucose absorption ↑ bowel movements Nervousness/tremor/insomnia Hyperreflexia Emotional lability Warm sweaty skin Fine/think hair Exopthalmos, opthalmaplagia Pretibial mxedema Osteoporosis Hyperthryoid storm HYPO Hypometabolic Galactorrhea, menorrhea, hyperPRL Hypercholesterolemia ↓ insulin secretion Wt gain Cold intolerance ↓ HR, SV, CO, PP ↑ PVR ↓ O2 consumption ↓ appetite ↓ glucose absorption ↓ bowel movements Lethargy Hyporeflexia (prolonged relaxation phase) Depression Cool dry/clammy skin Dry, brittle hair/nails, allopecia Periorbital edema Goiter Painful muscle cramps w/proximal myopathy Myxedema coma and death Pharmacology a. Adults require 150mg/day iodine, lower in kids, higher in pregnancy b. Amiodarone is leading cause of drug-induced hyperthryroid c. Hypothyroid lab values: high TSH due to loss of negative feedback (low T3/T4) d. Hyperthyroid lab values: low TSH due to negative feedback by high T3/T4 6 9. Hypothyroidism a. Developmental delays i. Earliest hypothyroidism results in worst results: cretinoid appearance, skeletal delays, mental retardation 1. Puffy hands/face, deaf mutism, jaundice, cyanosis, hoarse cry ii. Juvenile form spares mental retardation but delayed sexual maturation and ↓ school performance iii. Adult form, developmental delays do not occur, sx listed in clinical sx chart b. Tx: thyroxine (T4) replacement i. Myxedema coma: endstage untx’ed hypo, poor px mental status Δs, hypo-thermia/ventilation/glycemia/Na 1. 3 major features: CO2 retention/hypoxia, fluid/electrolyte imbalance, and hypothermia 2. Adrenal insufficiency likely to occur, automatically tx w/ glucocorticoids (hydrocortrisone) before replace T4 in ER TYPE Hashimoto’s thyroiditis 1° (inc. Hashimoto) Pituitary (2°) HMS (3°) Nutritional Medication-induced CAUSE Anti-TPO/TG Ab gradual destruction of thyroid gland Assoc w/ other autoimmune dz No T4 No TSH No TRH Iodine deficiency PTU/MMI, amiodarone, lithium CLINICAL Diffuse, firm, non-tender enlargement Hurthle cells (eosinophilic inclusions in lymphos) F>M (20:1) See clinical sx chart; most common Same Same Same + likely goiter due to HI TSH levels Usually resolves quickly following w/d 10. Hypothyroid tx a. Levothyroxine dosing i. Normal maintenance: 100-150 microg/d ii. Starting dose if young w/o longstanding dz OR >45y w/o cardiac dz: 50 mcg/d + titrate by 25-50 mcg/d iii. Starting dose if elderly OR have hx of cardiac dz: 12.5-25 mcg/d + titrate by 12.5-25 mcg/d DRUG Levothyroxine MOA Synthetic T4 replacement INDICATION DOC for hypothyroidism (can hyperthyroidism) Synthetic T3 Replacement When faster onset necessary SE/CONTRAINDICATION CV S/E (angina, arrhythmia) are dose limiting Steady state ~2mo, ↓ if thyrotoxicosis occurs Malabsorption (take in am on empty stomach) DDI: resin binders, E2 CV S/E 11. Hyperthyroidism a. Use uptake/scan to help differentiate i. HI uptake = excess hormone from thyroid vs LO uptake = ectopic hormone production or thyroiditis ii. Diffuse scan = Graves dz vs nodular scan = adenoma (hot nodule = functional/unlikely to be malignant) b. Tx: PTU/MMI, iodides, lithium, β-blockers, ablation (surgical or radio-iodine) c. Thyroid storm: extreme thyrotoxicosis (delirium, severe tachycardia, N/V/D, fever, dehydrat), poor px, medical emergency i. Tx w/ hydrocortisone, PTU/MMI, iodide (1h later!), propranolol TYPE Graves Disease CAUSE Anti-TSH R Ab mimic TSH & cause stimulation of thyroid (can cross placenta) Toxic Nodular Goiter Infxn inflamm, destruction of cells release of hormone Viral infxn → host tissue damage → auto-immune destruction in HLA-B35 individuals Autonomous nodule Subclinical hyperthyroidism Euthyroid but TSH depressed Ectopic thyrotoxicosis Ectopic hormone production via drugs, struma ovarii (teratoma) Acute thyroiditis Subacute Granulomatous Thyroiditis 12. Hyperthyroid tx Thioamide PTU, MMI Iodides Radioactive Iodide (RAI, I131) β-blockers CLINICAL Exopthalmos, pretibial myxedema, acropachy (clubbing due to new subperiosteal bone formation) Assoc with other autoimmune dz High uptake, diffuse scan, often goiter w/ bruit Painful thyroid, fever, eventual recovery Initially hyperthyroid, but once depleted, hypothyroid Acutely VERY painful thyroid (diffusely enlarged) Will spontaneously resolve, don’t need to Tx Low radioiodine uptake Goiter w/nodule(s) that are hyperactive (hot) Usually in elderly, no optho pathology Risk of atrial fibrillation and osteoporosis Amiodarone rich in I hyperthryroidism (-) TPO, coupling, T4T3 periph DOC kids/teens, preg, Graves (-) T3/T4 release, synth necrosis of hyperactive thyroid portions Controls cardiac sx Pre-op tx DOC old, heart dz, toxic nodules Maculopapular rash (try alternate) Hepatotox/agranulocytosis (do NOT try alt) Hypersensitivity, salivary/breast gland swelling Hypothyroidism can occur → monitor levels Give β-blockers to all pts 1st ↓ tremor, palps, anxiety 13. Neoplasms (papillary and follicular respond to tx w/ radioactive iodine, anaplastic does not) TYPE CLINCAL Follicular adenoma Benign, encapsulated, differentiated, very common middle aged euthyroid woman Papillary carcinoma Branching growth pattern, clear nuclei (orphan annie eyes), psammoma bodies Behavior/staging depends on age (generally good px even w/ local LN mets if ˂ 45y) (most common) Assoc w/ RET oncogene Follicular carcinoma Min invasive vs widely invasive, px better w/ former Insular carcinoma Nests of poorly differentiated tumor cells Anaplastic carcinoma Worst px, undiff tumor replaces gland, rare (see in elderly) Medullary carcinoma Neoplasm of para-follicular C cells w/ salt & pepper chromatin +/- amyloid (calcitonin) Strong assoc w/ RET oncogene (and MEN-2 syndrome) 7 PARATHRYOID/Ca HOMEOSTASIS 1. Parathyroid hormone (PTH; important for minute-to-minute Ca regulation) a. Stimulation: low Ca, high P, low VitD i. Calcium Sensing Receptor (CaSR) on parathyroid cells sense [], G-protein w/ multiple signaling ptwy (↑cAMP) b. Inhibition: high VitD via negative fb c. Effects i. Kidneys: ↑ Ca reabsorption, ↑ P excretion, activates 1-OHase (25-VitD 1,25VitD) ii. Intestines: active VitD ↑ absorption of Ca iii. Bone: ↑ osteoclast activity bone resorption, Ca release ↑ serum Ca d. Serum Ca levels can be ↑ by: i. ↑ intestinal absorption (via 1,25hydroxyVitD) ii. ↑ bone resorption (via PTH) iii. Inhibiting Ca renal excretion (via PTH) iv. ↑ pH (hyperventilation/metabolic alkalosis is associated with hypoCa) e. Serum Ca measurement via total Ca, which is dependent on albumin levels (since 80% bound) i. Corrected calcium (used if albumin abnormal) = measured total Ca + 0.8(4.2 – measured serum albumin) 2. Parathyroid also produces a compound PTHrP a. PTH-related peptide has sequence homology with PTH b. It is found physiologically in developing bone, in placenta, and in fetal tissues and acts as a paracrine factor c. Unlike PTH, it is NOT physiologically important in adult Ca homeostasis (only works in the fetus) d. However, it is secreted by various cancers pathologically and can lead to hyperCa 3. VitD (important for long-term Ca homeostasis) a. Stimulation: low Ca, low P, high PTH i. Defc’y due to low intake, low absorption, low UV exposure, PTH resistance b. Synth: 7-dehydrocholecalciferol + UV VitD3, which is constitutively hydroxylated by liver to 25-VitD3 (storage form, test of choice for defc’y), then kidney converts 25 1,25 VitD via PTH stimulation c. Effects: ↑ intestinal absorption of calcium, suppress PTH gene transcription 4. HyperCa a. Most commonly subclinical, but important to tx to prevent rare complications b. Sx: fatigue, depression, thirst, polyuria (osmotic diuresis), constipation c. Complications: osteoporosis/pathologic fx, kidney stones, life-threatening dehydration Dz Primary hyperPTH Familial hypocalciuric hyperCa PTHrP cancers Malignancy Vit D intoxication 5. PATHOGENESIS Adenoma/genetic high PTH ↑bone resorption ↑ Ca CaSR mutation makes receptor less sensitive to Ca PEARLS Most common cause Takes higher Ca to shut off PTH secretion PTHrP shares bone resorp fxn of PTH high Ca/low PTH Osteolytic mets (kidney, lung, thyroid, MM) resorb bone high Ca neg fb low PTH Excessive Ca intake/absorption ↑Ca neg fb low PTH Suspect if hyperCa in cancer pt Most common cause of non-PTH mediated hyperCa Measure 1,25vitD for dx of tox (vs 25vitD for defc’y) HypoCa a. Chronic well-tolerated vs acute assoc w/ parasthesias, spasms, tetany (partial depol of resting Vm hyperexcitability) b. Chvostek’s sign: twitch of upper lip toward side of tapped cheek c. Trousseau’s sign: acute pain/muscle clenching in arm/fingers following inflation of BP cuff for 3min Chronic Kidney Disease Autoimmune (most common), post-op, infiltrative (ex: malignancy) no/low PTH low Ca Renal failure no response despite high PTH low 1-OHase low VitD/low Ca Vit D deficiency PTH resistance Inability to absorb Ca despite high PTH Target tissue R mutation no response despite high PTH Gland destruction 6. 7. Most common cause hyperplasia of PTH gland Genetic disorder HypoP and HyperP a. Acute hypoP (due to VitD defc’y/resistance or alkalosis): muscle weakness (↓ATP), paralysis, rhabdomyolysis, hemolysis b. Chronic hypoP: bone pain/osteomalacia c. HyperP: ectopic calcification, pruritis, 1OHase suppression (→hypoCa), usually due to renal failure FGF23: hormone from osteocytes that ↑P excretion and inhibits 1OHase synthesis in kidney so excess causes hypoP/osteomalacia a. Degraded by PHEX, endopeptidase from gene on X chromosome 8 METABOLIC BONE DISEASE 1. 1°/2° hyperPTH bone loss (see ↑ telopeptides NTx/CTx, ends of type 1 collagen) subperiosteal erosions/cystic lesions on xray 2. Hyperthyroidism ↑ bone turnover RICKETS / OSTEOMALACIA Lack VitD defective bone mineralization (gene mutations exist, ex: 1-OHase defc’y) Can be hyperPTH w/↑osteoid/alk phos Can be excess FGF23 from tumor (TIO) PAGETS Dz Viral infxn of osteoclast localized disorder of bone remodeling Disorganized woven bone replaces lamellar bone, very fragile OSTEOPOROSIS Uncoupled bone remodeling Low bone mass risk for fx 1° forms= idiopathic in young, postmenopausal, senile Clinical Features “Soft” bone, bone/muscle pain + weakness Physical Findings Bone deformities (bowing w/ waddling gait) Delayed/absent calcification in zone of maturation, unmineralized osteoid Fragility fx, Dowager’s hump Tx: wt-bear exercise, bisphos, teriparatide, QUIT smoking! Ca/VitD for peak bone mass Low bone density on DEXA (T score <-2.5 = osteoporosis) (T score -2.5 to -1 = osteopenia) Radiology Tests Widened growth plate, concave metaphysis Looser zones: pseudofractures (tender) Affects adults, middle aged men Enlarged, painful, brittle bone Can cause hearing loss, heart failure Tx: bisphos, calcitonin Vascular steal syndrome Osteosarcomas (30x ↑ risk) ↑ alk phosph Cranial nerve palsys, frontal bossing Sclerotic bone w/ shaggy lytic areas Definition OSTEOGENESIS IMPERFECTA Defective Type 1 collagen production → weak bone w/ ↓ mass → fx, deformity OSTEOPETROSIS Osteoclast defc’y → overgrowth/sclerosis of cortical bone Clinical Features fx, blue sclera, brittle teeth, hearing loss Tx: bisphos Pathologic fx, poor tooth eruption, anemia (↓ marrow cavity), vision/hearing loss (CN compression) CKD MINERAL/BONE DISORDER ↑PTH → osteitis fibrosa cystica ↓VitD → osteomalacia Together → mixed uremic osteodyst 2° to dialysis (β2 microglob amyloid) Abnormal Ca homeostasis Biopsy for definitive dx Definition Radiolucent porous bone OBESITY 1. Definition: excessive body weight assoc w/ adverse health a. Central obesity: ↑ waist circumference – M >40in, F >35in (best indicator) i. ↑ visceral fat release of hormones/cytokines that ↑ insulin resistance b. BMI: ratio of height and weight (kg/m2) or [(lbs/2.2)/(ft*0.3)2] i. 18.5-25 normal ii. 25-30 overweight iii. 30-35 obese type I iv. 35-40 obese type II v. >40 morbidly obese 2. Epidemiology: >20% of adults are obese, esp AA 3. Consequences a. ↑ morbidity & mortality – @ risk for metabolic syndrome, arthritis, gall bladder disease, endocrine cancers, HTN, CAD, DM i. Metabolic syndrome: excessive intake of food + thrifty genes, which try to conserve energy obesity, insulin resistance ii. Adipocyte secretions: ↑ IL-6/TNF- (pro-inflamm) + ↓ adiponectin release (→ insulin resistance) iii. Dx: 3/5 of: 1. Central obesity 2. TG >160 3. HDL <40 (M), >50 (F) 4. HTN 5. Hyperglycemia 4. Weight regulation a. Complicated by genetics, biological predispositions b. Energy expenditure i. BMR: energy cost of homeostasis (65%) ii. Physical activity (30%) – low activity is biggest cause of obesity iii. TEF (thermal effect of food): energy cost of digestion (5%) c. Hormones i. ↑ appetite/↓ energy expenditure: Neuropeptide Y (NpY R in HMS), Orexins, Ghrelin (from stomach, modulates NpY) ii. ↓ appetite/↑ energy expenditure: Leptin (from adipose to HMS), POMC/MSH (bind melanocortin4 R or MC4 R) 1. Note: most obese have paradoxically ↑ leptin → suggests leptin resistance d. Drugs can lead to weight gain (diabetes meds, corticosteroids, OCP) 5. Management a. Lifestyle changes (moderately overweight) i. 500cal/day reduction + exercise, esp important for T2DM b. Pharmacologic changes (overweight with risk factors, or obese) i. Sibutramine (5-HT, NE reuptake inhibitor or SNRI); S/E: ↑HR/BP ii. Phentermine (NE agonist) iii. Orlistat (inhibit pancreatic lipase to ↓ fat absorption); S/E: soft stool/anal leakage/↓ fat-soluble vitamin absorption c. Surgical Management (BMI 35-40 w/ risk factors or morbid obesity) i. Roux-en-Y gastric bypass (gold std), very effective in weight loss/elimination of DM/asthma/HTN/sleep apnea 1. Basically cut off fundus of stomach (esophagus attached) and attached directly to s. intestine 2. Pt must understand procedure and commit to long-term F/U 3. Watch for vitamin deficiencies (esp. Fe/Ca/thiamine/VitD/VitB12) ii. Liposuction can be dangerous and has not been shown to improve metabolic/CV risk 9 HYPERLIPIDEMIA 1. Lipoproteins a. Enable transport of insoluble lipids via complexing w/ proteins b. Cores of hydrophobic lipids (TG, cholesterol) + surface layer of hydrophilic proteins/phospholipids 2. Apolipoproteins a. Protein moiety on lipoprotein surface that (1) helps solublize lipids + (2) acts as R ligands that direct to specific target cell b. Responsible for LDL R-mediated clearance of LDL particles i. LDL R recognizes Apo-B100, Apo-E ONLY; thus, mutation no uptake very high serum chol levels c. Lp(a) – an LDL particle linked to apoprotein (a); is an independent risk factor for AS and CAD LIPOPROTEIN Chylomicron VLDL IDL LDL HDL 3. 4. 5. 6. TRANSPORTS TG TG cholesterol cholesterol APOLIPOPROTEIN Apo-B48, Apo-E, Apo-C2 Apo-B100, Apo-E, Apo-C2 Apo-B100, Apo-E Apo-B100 only Apo-A NOTES Exogenous pathway (intestine), degraded LPL Endogenous pathway (liver), degraded LPL VLDL IDL LDL Carries chol to tissues Carries chol from tissues back to liver Exogenous pathway: fat in intestine chylomicrons lympatics to peripheral tissue (energy), liver (as remnants) Endogenous pathway: liver converts lipids into VLDL for energy for body IDL/LDL via LPL in adipocytes/myocytes/MΦ a. LPL mutation inability to extract TG from chylomicrons for use in tissues very high serum TG levels b. LCAT (formation of cholesterol esters) and CETP (removes cholesterol from HDL) enzymes convert chol into various forms Atherosclerosis : lipid deposition cellular proliferation and inflammation reduces blood flow/ischemia a. High calorie/fat intake high VLDL production from liver b. High VLDL high LDL in circulation both by more production and down-regulation of LDL receptor (thus, less removal) c. High LDL deposition into intima, where oxidized/taken up by scavenger R of MΦ d. Foam cells (MΦ filled w/ cholesterol) release inflammatory cytokines more MΦ + prolif of smooth muscle cells e. Tunica media becomes filled w/ foam cells and hypertrophied/hyperplastic smooth muscle vessel narrowing f. Thrombogenic surface clot formation Pancreatitis: due to severe hyperTG (>1000 mg/dL) membrane breakdown, leakage of enzymes inflamm + autolysis 7. Primary lipoproteinemias Dz MOA AutoD LDL R mutation high LDL Familial family hx hypercholesterolemi a Familial combined hyperlipidemia Type III hyperlipoproteinemia LPL defc’y AutoD unknown high TG + LDL family hx AutoR Apo-E mutation defective binding CM/VLDL/IDL remnants to LDL R AutoR LPL mutation ↓ clearance of chylomicrons (thus, HIGH TGs) Apo CII defc’y Familial hyperTG AutoR Apo-CII mutation (LPL cofactor) AutoD unknown very high VLDL/TG 8. Secondary lipoproteinemias Insulin defc’y impaired LPL Uncontrolled DM activity impaired removal of circulating lipoprots Hypothyroidism Impaired clearance of LDL ↑ VLDL synth in liver Alcoholism and estrogen therapy Proteinuria liver produces more of Nephrotic syndrome everything, including VLDL/LDL Drugs 9. Tx a. b. CLINICAL Heterozygote: common, premature CHD, xanthelesmas (near eye), tendon xanthomas, arcus corneae, LDL <500mg/dL Homozygote: rare, CHD early childhood, planar xanthoma in addition to sx for heterozygote, LDL 500-1000mg/dL Premature CHD but NO xanthomas/xanthelesmas High [] of cholesterol remnants cholesterol ~300mg/dL Premature CHD, palmar xanthomas Heterozygote: resembles 2° lipoproteinemia Homozygote: early childhood, pancreatitis, hepatosplenomegaly, lipemia retinalis, eruptive xanthomas Resembles LPL defc’y Assoc w/ obesity, insulin resistance High TG, LDL Low HDL High LDL (screen pts for hypo), but responds well to thyroid HRT Both also ↑ HDL Protease inhibitors, glucocorticoids, androgens Screening: fasting lipid profile for all adults >20y, if normal, repeat every 5y Diet: esp for those w/ CHD → ≤30% of total calories from fat (<7% saturated fat) + <200mg/d cholesterol DRUG HMG-CoA reductase inhibitors (statins) Bile acid seq Fibric acid derivs Niacin MOA (-) rate-limiting step in chol synth + up-regulation of LDL R Resins exchange Cl for bile acids Bile acid loss to feces causes liver to use chol to make more (↑LDL R) Unknown, assoc w/PPAR activation Unknown Ezetimibe Ileal Bypass Surgery (-) chol absorption @ brush border (-) chol absorption INDICATION DOC to ↓ LDL SE / CONTRAINDICATION Myalgias, myopathy Adjunct to statins to ↓ LDL Bloating, constipation ↓ TG ↓ LDL/TG/Lp(a) ONLY one that ↑ HDL Adjunct to statins to ↓ LDL Severe hyperchol and failed other tx Myalgias, myopathy, rare hepatotox Flushing syndrome, rare hepatotox 10 DIABETES 1. Definition: abnormalities in CHO/protein/fat metabolism due to lack of/resistance to insulin hyperglycemia + microvascular dz (retinopathy, neuropathy, nephropathy) + macrovascular dz(accelerated AS) + freq HTN/dyslipidemia 2. Epidemiology: >21 million in US (95% of which is type II), more prevalent in minorities 3. Insulin a. Synthesis: via β-cells in central portion of Islet of Langerhaans in 1:1 ratio of insulin + C-peptide b. Secretion: in response to ↑ blood glucose i. Glucose enters β-cell via GLUT-2 (glucose independent) 1. First phase due to release of preformed insulin, thus immediate 2. Second phase due to preformed insulin AND de novo synthesis, thus slower ii. Inhibition: GGCC (Glucagon from -cells, GH, Cortisol, Catecholamines) c. Effects: major anabolic hormone in the body i. Stimulates synthesis (+ inhibits degradation) of glycogen, proteins, and lipids 1. Liver - ↓ GNG, ↑ glycogen synthesis/lipogenesis 2. Fat - ↑ fat uptake/lipogenesis 3. Muscle - ↑ glucose uptake/glycogen synthesis/protein synthesis 4. Brain/RBCs - use glucose but uptake is not insulin-dependent GLUT-4, i.e. glucose level independent ii. MOA 1. Binding of insulin to -subunit of insulin R autoP of β-subunits tyrosine kinase activation cascade a. Insulin R is NOT a GPCR b. PIP3 pathway: translocation of GLUT-4 to cell membrane ↑ glucose uptake in muscle/fat c. MAP Kinase pathway: cell growth, proliferation, altered DNA activity d. Leprechaunism: due to homozygous mutation in insulin R gene (rare) 4. Dx a. 1/4 criteria needed i. Random glucose >200mg/dL + classical sx (polyuria, polydypsia, nocturia, wt loss) ii. Fasting glucose >126mg/dL on two separate occasions (normal is ˂100mg/dL) iii. OGTT >200mg/dL @ 2hrs post-prandial (normal is ˂140mg/dL) iv. HbA1c ˃6.5% 5. Classification of Diabetes Genetic assoc Key sx Type of destruction °of insulin deficiency Req exogenous insulin? DKA common? Obesity common? Age of onset? a. 6. Type 1 i. ii. Type 2 i. ii. Type 1 Weak, assoc with HLA-DR3/4 Micro/macrovascular, polyuria/dypsia, wt loss Autoimmune (T cell mediated) Absolute Completely dependent on exogenous insulin Yes Rarely obese, weight loss is common Often younger, quick presentation Type 2 Very strong, family hx common Insidious onset, mainly MACROvascular (ex) AS Amyloid deposition/degeneration of β-cells Relative May be necessary in late stages/uncontrolled Rare, HHNKC is more common Usually obese Often older, insidious presentation Diabetes Anti-insulin Ab, anti-islet Ab, anti-GAD Ab are MARKERS of dz, not the cause Sx begin with >90% β-cell destruction (i.e. years after hypersensitivity has begun) b. Diabetes No 1st response (the one where preformed insulin released), but normal 2nd response Body tries to compensate by ↑ endogenous insulin synth/secretion, eventually, β-cell failure low insulin 1. Basal level of insulin remains – enough to prevent ketosis but not enough to prevent hyperglycemia iii. In early stages, if glucose is effectively lowered, insulin sensitivity returns (cure glucose toxicity) c. Impaired Glucose Tolerance (pre-diabetes) i. Dx via meet 1/3 criteria: 1. Fasting glucose 100-125mg/dL 2. 2hour OGTT 140-200mg/dL 3. HbA1c 5.7-6.4% d. Gestational DM: 3hour OGTT results with at least 2 of: 1 hour (>180), 2 hours (>155), 3 hours (>140), fasting (>95) Acute complications a. DKA i. Rare, but an emergency medical condition seen in type 1 DM, often precipitated by infxn ii. Absolute insulin deficiency + high glucagon catabolic state 1. Muscle releases AA (substrate for GNG), fat releases FFA (substrate for ketogenesis) a. Marked ↑ GNG extreme hyperglycemia i. ↑ sugar high filtered load that exceeds resorptive capacity of kidney unreabsorbed glucose acts as osmotic diuretic in urine polyuria vol depletion ii. Low volume ↓ renal blood flow acute renal failure b. Excess FFA ketones, which are acidic, thus acidosis i. Body ↑ respirations to blow off excess CO2 (from excess H) = Kussmauls breathing 2. Sx: polyuria, N/V, fruity breath odor (acetone) 3. PE: low BP, high HR, high RR, dry mucous membranes/soft eyes due to dehydration 4. Labs: high Hb (hemo[]ed), high BUN/Cr, low arterial pH b. Hyperglycemic Hyperosmolar Non-Ketotic Coma (HHNKC) i. Seen in type II DM due to relative insulin defc’y ii. Low insulin levels sufficient to prevent ketone body production but insufficient to prevent hyperglycemia iii. Ppt factor (drank gallons of Coke to satisfy polydipsia) extreme hyperglycemia osmotic diuresis extreme dehydration but NO KETOSIS coma predictable sx, lab values 1. Liver thinks glucose is low (b/c intracellular glucose IS low) GNG/glycogenolysis which exacerbates problem c. Hypoglycemia (due to excessive insulin) 11 7. 8. Chronic complications a. Elevated HbA1C (marker of long-term glucose status, good way to determine if pt is compliant w/ therapy) b. Macrovascular (main complications) i. Begin early, with start of insulin resistance ii. Ex: AS CAD (#1 killer complication of diabetes) + PVD c. Microvascular i. Begin later, with hyperglycemia ii. Most likely caused by non-enzymatic glycosylation due to all the excess glucose (formation of AGEs) iii. Ex 1. Retinopathy: capillary hemorrhage ischemia neovascularization prone to bleeding blindness 2. Nephropathy: thickening of glomerular caps destruction of membrane micro/macroalbuminuria RF 3. Neuropathy: esp in distal hands/feet 4. Poor wound healing Pharmacology – hypoglycemia is always a potential SE! a. Type 1 has absolute requirement for exogenous insulin i. Types of insulin 1. Rapid acting for use before meals: Aspart, Lispro, Glulisine 2. Short acting: regular insulin 3. Intermediate acting: NPH, Lente 4. Long acting to maintain basal level (prevents ketosis): Ultralente (small peak), Glargine, Detemir Ultralente /Detemir b. ii. iii. Type 2 i. ii. MOA: replaces non-existent insulin, suppresses hepatic GNG, ↑ glucose uptake by GLUT4 tissues Indication: DOC for type 1, may be necessary in late stage type 2 Non-pharmacological tx is first (lifestyle changes) Oral hypoglycemics DRUG IV Fluids Sulfonylureas Glipizide Glyburide Glimepiride Biguanides Metformin MOA Replacement of fluid and electrolytes ↑ insulin secretion by triggering pre-form insulin release (SU R, K-channel), “secretagogue” INDICATION Esp w/ DKA, HHNKC Type 2 DM Lean pts ( wt gain) ↓ hepatic GNG Obese + insulin resistance Hx of hypoglycemia PCOS Thiazolidinediones -glitazones ↓ insulin resistance (bind PPAR ↑ GLUT4) ↓FFAs Meglitinides -glinides -Glucosidase (-) Acarbose Miglitol Incretins Pramlintide ↑ insulin when glucose exceeds a threshold (so effect is glucose [ ]-dependent) Slows GI breakdown/absorption of complex CHO Insulin resistance Hx of hypoglycemia PCOS Type 2 DM Sitagliptin (-) DPP-4, the enzyme which deactivates GLP-1 (an incretin) GLP-1 analog, resistant to DPP-4 Exenatide Amylin analog, a normal gut protein delayed emptying, satiety, ↓ glucagons, ↓ GNG Postprandial hyperglycemia Severe hypoglycemia due to tx w/SUs Type 2 DM Type 1 DM - add to insulin SE / CONTRAINDICATION Type 1 DM (no β-cells to respond) Glyburide contra: renal insufficiency (↑ risk of hypoglycemia) DDI: EtOH, NSAIDs, E2, β-block, etc Contra: renal/hepatic dz, CHF (↑ risk lactic acidosis) GI effects DDI: furosemide, cimetidine, digoxin Contra: CHF (↑ plasma vol) ↑LFTs, wt gain, ovulation, edema Hypoglycemia/HA DDIs: erythromycin, rifampin, ketocon GI effects, flatulence Glucose tablets for hypoglycemia (complex carbs not absorbed!) Nausea Take immediately before meals and lower insulin dose by 50% Type 2 DM Type 2 DM Combo w/ SU, metformin Nausea Take 60min prior to meals Contra: severe kidney dz 12 FEMALE REPRODUCTIVE 1. Pubertal Development a. Thelarche (breast budding/glandular development), starts ~8y b. Adrenarche (pubic/axillary hair) and growth spurt c. Menarche (as growth spurt decelerates), starts ~12y and first 1.5y may be anovulatory 2. Review a. Hypothalamus releases pulsatile GnRH FSH/LH release from pituitary E/P/A from ovary b. Ovarian follicular phase is correlated with endometrial proliferative phase; ovarian luteal assoc with endometrial secretory phase c. Rising estrogen/progesterone lead to LH surge, and ovulation follows ~24h later d. During luteal phase, high estrogen/progesterone (PG) prepare endometrium (secretory phase) i. w/o implantation (w/o hCG to replace LH, which is ↓ due to ↓ GnRH pulses) luteal degeneration (↓PG) menses e. Follicle anatomy: w/in are granulosa cells (FSH receptors), outside are theca cells (LH receptors) f. FSH roles i. Stimulates granulosa cell proliferation and E2 formation (via aromatase, from testosterone produced by theca cells) ii. Upregulates FSH + LH receptors g. LH roles i. Stimulates testosterone formation in theca cells ii. LH surge: midcycle, causes follicle to undergo meiotic change Amenorrhea Primary Amenorrhea, high FSH Turner Syndrome (45, XO) Testicular feminization syndrome (46, XY) Anatomic Problems HMS/Pituitary Problems 2° Amenorrhea w/↑ FSH 2° Amenorrhea w/o ↑ FSH 3. 4. 5. 6. Pathogenesis Ovary does not respond to FSH Pre-pubertal destruction (chemo), chromosomal dysfxn Accelerated postnatal follicular atresia nonfxn ovary High FSH/LH XY male w/ AR mutation make androgen but can’t respond to it, female external phenotype Have internal testes, blind-end vagina Various anatomic problems that prevent normal menstruation, dx by estrogen/progestin challenge Lifestyle: excessive exercise, stress, morbid obesity Organic: Kallman’s, pituitary tumor Ovary destruction (ex chemo) acquired ovary failure Anatomic (scarring)/HMS/pituitary problem acquired ovarian failure, dx by estrogen/progestin challenge Clinical Amenorrhea and lack of 2° sex-characteristics first via history, then order a karyotype No secondary sex characteristics Webbed neck, wide-spaced nipples, low hairline Undergo thelarche but NO adrenarche/menarche Testes still secrete Müllerian inhibit substance Testes must be removed to prevent cancer Ovarys make estrogen normal 2° sex Tx by surgery Endocrine imbalance lack normal 2° sex Tx by hormonal supplementation Estrogen HRT can be used Tx by surgery for anatomic Tx by hormonal replacement for HMS/pituitary Menstrual disorders a. Amenorrhea i. Normal mensturation: 4 weeks plus/minus 1 week (poly/oligo-mennorrhea) 1. Menorrhagia – excessive bleeding 2. Menometrorrhagia – chaotic non-periodic bleeding ii. Primary amenorrhea: a woman who has never menstruated (age 18, or by 16 if sex-characteristics are lacking) iii. Secondary amenorrhea: a women who has menstruated but now does not (6 cycles or 3 intervals) iv. Dx: primary or secondary? check FSH → if high, the problem is w/ the ovary not responding b. Dysfunctional Uterine Bleeding – endometrium is responding normally to abnormal endocrine signals i. Functional Problems 1. Anovulatory cycles – most common cause of DUB during reproductive years a. failure of ovulation loss of progesterone, thus unopposed estrogen stimulation 2. Endometrial atrophy is most common cause in postmenopausal women ii. Organic Problems such as polyps Hyperandrogenic Disorders a. Women secrete androgens from two sites: adrenals (zona reticularis) and ovary b. Circulating androgens – free form is active form, levels ↑ with high estrogens (which also bind SHBG) c. Types of androgens that can be over-produced i. DHEAS – made by adrenals, so elevations point toward adrenal overproduction ii. Testosterone – most potent, elevations w/o DHEA elevations point toward ovarian problem d. Dx i. Elevations of DHEAS = adrenal overproduction: adrenocortical carcinoma, Cushings, CAH (congenital adrenal hyperplasias) – late onset form is very common and usually involves 21-hydroxylase defc’y (tx w/ glucocorticoids) ii. Elevations of testosterone w/o elevation of DHEAS = ovarian problem 1. Ovarian neoplasm (very high testosterone levels) 2. Polycystic Ovarian Disease a. Overstimulation of theca and under-aromatization hyper GnRH release from hypothalamus b. Abnormal LH/FSH is key ↑ androgens, ↓ estrogen hormonal and metabolic imbalance c. US shows multiple cysts e. Sx of excess androgens: oligo or amenorrhea, hirsutism (irreversible conversion vellus→terminal hair), obesity, insulin resistance f. Tx: treat source of hyperandrogenism w/ 5-reductase inhibitors (finasteride), AR antag (spironolactone, ketoconazole), flutamide Pathophysiology of hyperprolactinemia /galactorrhea a. Prolactin = pituitary hormone that regulates lactation, tonically inhibited by dopamine (prolactin inhibitory factor) b. Prolactin ↑ during pregnancy involved in milk production not milk let-down (that’s oxytocin) c. Galactorrhea is an inappropriate bilateral discharge of milk (unassoc w/ childbirth or nursing) d. Causes of hyperprolactinemia: ↓ dopamine in CNS (neuroleptics), hypothyroidism, pituitary tumors (may be removed → transspenoidal resection), stalk compression such that PIF doesn’t reach target, chest wall trauma, nipple stimulation e. Tx: dopamine agonists (ex) bromocriptine, cabergoline Infertility Medicine a. Infertility: 1 year of regular unprotected intercourse not resulting in conception (normal monthly probability of fertilization ~20%) b. Male problems – central (pre-testicular), testicular, post-testicular c. Female problems – dysfunction vs failure, anatomical obstruction 13 FEMALE PATHOLOGY 1. Infections a. Chlamydia – gram neg intracellular, most common STD, neonatal conjunctivitis, can infertility b. Gonorrhea – gram neg diplococcus, ascending infxn leads to scarring c. Herpes – must delivery babies of herpes+ mothers by C-sxn to prevent transmission (often fatal), ulcerated vesicles d. Trichomonas – large flagellated protozoan easily seen in wet mount, see “strawberry cervix” e. Candida – exacerbated by pregnancy, OCP (oral contraceptive pill), and diabetes, hyphae/pseudohypae, curd-like discharge f. Gardnerella vaginalis – very common, gram (-) bacillus, fishy odor 2. Vulva a. Epithelium is stratified squamous b. Lichen Sclerosus – dermal sclerosis, may be autoimmune, often older women, little inflammation, no rete ridges c. Lichen Simplex Chronicus – epithelial hyperplasia and hyperkeratosis → white patches, may have inflamm infiltrate d. Vulvar Intraepithelial Neoplasia (VIN) = HPV i. Mild dysplasia: squamous, assoc with low risk HPV (6,8,11)→ condyloma acuminatum (warts) ii. Severe Dysplasia: assoc with Paget’s disease (owl eye cells) or melanoma (non-squamous) 1. Don’t know where malignant cells in vulvar Paget’s come from (vs from DCIS in nipple Paget’s) 3. Cervix a. Ectocervix = stratified squamous while Endocervix = columnar (mucin secreting) b. Squamous epithelium meets glandular epithelium at squamocolumnar junction (SCJ) c. Cervical Intraepithelial Neoplasia (CIN) = HPV (CIN much more common than VIN) i. Squamous metaplasia of columnar cells at SCJ ii. Due to high risk HPV (16,18,31) and can result in transformation to invasive cancer 1. Can adenocarcinoma in situ or invasive adenocarcinoma iii. Risk factors: multiple sex partners!! iv. Classification (Bethesda System building on CIN system) 1. LSIL (low grade squamous intraepithelial lesion) = CIN 1 = mild dysplasia 2. HSIL (high grade SIL) = CIN 2,3 = moderate or severe dysplasia including carcinoma in situ v. Pathology: koilocytes vi. Screening: Pap smears 4. Uterus a. 3 layers: serosa, myometrium (muscular layer), endometrium b. Menstrual cycle i. Days 1-4: Menstrual Phase ii. Days 4-14: Proliferative Phase – REQ ESTROGEN, prolif of stroma iii. Days 15-28: Secretory Phase – REQ PROGESTERONE, spiral arteries c. Endometritis (inflammation) i. Acute is usually due to ascending infxn thru cervix, see PMNs ii. Chronic assoc w/ PID (esp chronic gonorrhea), see fibrosis and mononuclear cells, must see plasma cells d. Dysfunctional Uterine Bleeding – endometrium is responding normally to abnormal endocrine signals i. Functional 1. Anovulatory cycles – most common cause during reproductive years a. Failure of ovulation don’t get progesterone, thus unopposed estrogen stimulation 2. Inadequate luteal phase – corpus luteum forms but is wimpy 3. Endometrial atrophy – most common cause in postmenopausal women ii. Organic 1. Polyps, leiomyoma, hyperplasia, carcinoma e. Endometrial Hyperplasia i. ↑ gland:stroma ratio ii. ↑ risk of developing into carcinoma iii. Pathology (+/- atypia) 1. Simple – cystic, large bubbles 2. Complex – papillary projections of glands, carcinoma-in-situ risk of progression to carcinoma iv. Causes (extra estrogen stimulation): anovulation, PCOS, granulosa cell tumors, obesity f. Benign Polyps - most common endometrial tumor, usually solitary, more common post-menopause, usually present w/ bleeding g. Endometrial Carcinomas i. Type 1 (endometrial type) 1. Obese, assoc w/ high estrogen, low grade/good px ii. Type 2 (serous & clear-cell type) 1. Older women, skinny, no association with estrogen, high grade/poor px, see Hobnail cells iii. DES medication use in mother clear cell VAGINAL carcinoma in daughter iv. Other factors: cervical invasion ↑ the stage, vascular invasion ↑ metastatic risk (NO effect on stage tho) 1. Stage is most important indication of px a. 1= confined to uterus b. 2= involves cervix c. 3= outside uterus, but not outside pelvis d. 4 = outside pelvis h. Myometrium i. Leiomyoma 1. most common benign uterine tumor, very common in reproductive women 2. Location is intramural, submucosal, sub-serosal ii. Leiomyosarcoma 1. Does not arise from pre-existing leiomyomas 2. Aggressive w/ mets to lung and often recur after removal 3. Best predictors of malignant behavior: mitotic activity/necrosis/nuclear atypia iii. Adenomyosis 1. Endometrium glands and stroma inappropriately located w/in myometrium, very painful 14 5. Ovary a. b. c. Polycystic Ovary Syndrome i. Triad: obesity/insulin resistance, hirsutism, amenorrhea/oligomenorrhea ii. Common cause of infertility iii. Due to excessive secretion of GnRH excessive LH (but not FSH) → excessive androgen secretion iv. Ovaries have sclerotic capsules (“great white ovaries”) and cysts lined by thick theca interna Endometriosis i. Ovary is the most common site, very painful, “chocolate cyst” Ovarian Tumors i. Ovarian cancers have highest mortality rate of any female genital cancers due to late detection ii. Predisposing risk factors: many, none of which is more harmful than the other 1. Pts with BRCA1/2 mutations will likely get breast/ovarian cancers, but have better chemo-sensitivity iii. Surface Epithelial-Stromal Tumors 1. Most common tumors of ovary 2. Assoc with BRCA1 ovarian tumors 3. Types a. serous tumors: most common type, huge cyst, psammoma bodies (calcified lamellar concretion) b. mucinous tumors: multiloculated cysts c. clear cell carcinomas are epithelial tumors assoc with endometriosis, hobnailing d. Brenner tumor: dense fibrous stroma w/ nests of urothelial cells w/ coffee bean nuclei 4. Grades a. Benign: serous cystadenoma most common b. Borderline tumor: proliferative but good px, no invasion into stroma i. Pseudomyxoma peritonei – enlarged abdomen filled w/ gelatinous goo, tumor of appendix c. Malignant: poor px, invasion into stroma i. Serous carcinoma most common, psammoma bodies iv. Sex Cord-Stromal Tumors 1. Granulosa Cell Tumors a. ↑ estrogen endometrial hyperplasia (or carcinoma) b. Postmenopausal women c. Call-Exner bodies – granulosa cells haphazardly surrounding cyst filled with eosinophilic fluid d. Coffee bean nuclei 2. Thecoma-Fibroma a. Usually benign and unilateral in older women b. Thecomas are stromal cells w/ lipid droplets (functional) c. Fibromas are hard fibrous tissue (non-functional) d. Meig’s syndrome: ovarian tumor + hydrothorax (often R side only) + ascites v. vi. vii. 6. Sertoli/Leydig Cell Tumors 1. Homologous to testicular cancer 2. Usually low malignant potential, usually unilateral 3. See in young virilized women 4. Secrete androgens Germ Cell Tumors 1. Children, very aggressive, but chemo-sensitive 2. Teratoma: mature type are benign; immature type are malignant, dermoid cysts most common (tissue from all 3 germ layers including things like hair/teeth) 3. Yolk sac tumors: Schiller-Duval bodies, elevated -fetoprotein Metastatic carcinoma 1. Breast, lung, stomach, GI 2. Bilateral 3. Krukenberg tumors: from stomach, aka “signet-ring” tumor cells filled w/ mucin Placenta a. Clinical problems assoc with placenta: IUGR, congenital abnormalities, maternal/fetal morbidity, maternal/fetal/infant death b. Disorders of placenta i. Abnormalities of placentation 1. Placenta accreta a. Abnormally deep adherence of placenta to myometrium due to no decidua basalis b. risk is rupture, hemorrhage when placenta detaches→ need surgery c. Accreta is superficial myometrium, incerta is intermediate, and percreta is extension thru uterine wall 2. Placenta previa a. Implantation near region of cervix prevents normal separation b. Results in postpartum hemorrhage/uterine rupture 3. Abruptio placenta a. Premature separation of placenta (which was normally situated) b. May result in retroplacental hematoma (a complication seen w/ pre-eclampsia) ii. Ascending infections (bacterial, can chorioamnionitis and funisitis (umb. cord)) vs hematogenous (viral) 1. Complications: premature rupture of membranes or preterm labor iii. Gestational trophoblastic disease = hydatidiform moles (risk higher if ˂15y or ˃40y, and for asians 1. Complete: no fetus, all villi involved (hydropic changes so villi look like grapes, trophoblastic prolif/atypia), Karyotype is diploid (XX, both from father), can choriocarcinoma (check hCG) 2. Partial: fetus is present, only some villi are affected, karyotype is triploidy (XXY, 1 mom and 2 dad) a. Less trophoblast prolif and no atypia, less hCG and choriocarcinoma rare 3. Choriocarcinoma spreads hematogenously to brain/GI/lung/liver, produces hCG, responds to chemo 15 7. Fallopian Tubes a. Salpingitis (inflammation) i. Acute due to ascending infxn (E.coli, N.gonorrhea, Chlamydia, Mycoplasma) 1. N.gonorrhea causes pus formation (pyosalpinx) and can lead to PID ii. Chronic due to repeat episodes of acute (esp subclinical Chlamydia) 1. Complications include obstruction → infertility/ectopic pregnancy/hydrosalpinx/PID b. Salpingitis Isthmica Nodosa i. Isthmus of tube has diverticula ii. May result in infertility/ectopic pregnancy c. Ectopic Pregnancy (1/200 live conceptions) i. 95% in fallopian tubes and ½ of these due to impedance of flow thru tube ii. Trophoblasts permeate wall leading to hematosalpinx and potentially dangerous intraperitoneal hemorrhage d. Malignant Tumors i. Usually mets from ovary/uterus ii. Primary tubal carcinoma is rare and asymptomatic, so dx late w/ poor px BREAST PATHOLOGY 1. Drainage & Supply a. Lymphatic drainage 85% to axillary lymph nodes, rest to internal mammary; important for metastasis i. Level 1 = lateral to pec minor ii. Level 2 = deep to pec minor insertion on coracoid process iii. Level 3 = medial to pec minor b. Arterial supply: internal mammary (from subclavian), axillary artery perfuses lateral periphery, least perfused is lateral inferior c. Innervation: intercostal n (nipple is by 4th intercostal nerve), intercostobrachial most often damaged during axillary node removal d. Cyclic menstrual changes due to E/P: ↑ cellular proliferation, ↑ acini #, “premenstrual fullness” e. Changes due to pregnancy: dramatic hyperplasia of all cell types f. Changes due to menopause: atrophy 2. Terminal Duct Lobular Unit (TDLU) – functional unit, structure from which most breast diseases arise 3. Characterization of breast masses: a. 5Cs: count/consistency/contour/character/clock (to assess masses/lumps) b. 4Ds: dominant/discrete/dense/different (to determine true lumps from lumpy areas) 4. Benign dz a. Mastalgia – breast pain i. Usually cyclical, hormonal, high caffeine ii. Tx is conservative (↓caffeine, take VitE/primrose oil) b. Fibrocystic Change i. Breast pain, swelling, tenderness ii. Usually nothing but need to rule out breast cancer c. Nipple Discharge i. Bloody discharge – usually need to excise the duct, rule out Pagets d. Mastitis i. Backed up milk → staph infection ii. Think: Could this be an inflammatory breast cancer? biopsy after 1 wk of symptoms/no improve w/ABx e. Duct Ectasia i. Subareolar ductal dilatation w/ fibrosis and inflammation, may respond to ABx but often need excision of duct 5. Benign epithelial lesions a. Presenting w/ nodules (size, tenderness?) and nipple discharge i. Discharge color: 1. Milky-white (galactorrhea) 2. Sanguineous (intra-ductal papilloma) 3. Green (bilateral, reassure pt could just be an infxn) ii. Most worrisome: unilateral, spontaneous, single-duct, bloody discharge b. Types i. Risk is elevated with family hx of breast cancer and ↑ age of pt ii. Non-proliferative fibroblastic change (1% ↑ risk) 1. By far the most commonly detected lesions in the breast a. Fibrosis b. Adenosis c. Apocrine metaplasia: change in cell type, repro age women, normal response to abnormal stimuli d. Fibroadenoma e. Simple cysts: dilated ducts iii. Proliferative Fibrocystic Changes w/o Atypia (2% ↑ risk) 1. Typical ductal hyperplasia – cells look normal, just hyperplastic 2. Papillomas – intraductal papilloma, a core of vessels surrounded by proliferation 3. Sclerosing adenosis – extra tissue in lobules 4. Radial scar/complex sclerosing lesion (same except scar is ˂1cm) 5. Mondor’s dz – thromboplebitis of superficial thoracoepigastric vein → painful palpable cord (give NSAIDs) 6. Fat necrosis – can mimic cancer, assoc w/ recent trauma, tx w/ NSAIDs iv. Proliferative Fibrocystic Changes w/ Atypia (5% ↑ risk) 1. Atypical ductal hyperplasia - duct is lined by abnormal cells 16 6. Breast Carcinoma a. 1/8 of women, ↑ by late age 1st childbirth, obesity, family hx, HRT, early menarche (˂11y), late menopause (˃55y) b. BRCA1 (Ch17) > BRCA2 (Ch13) (both DNA repair enzymes), assoc with pre-menopausal breast/ovarian cancer i. Carriers have 85% of developing cancer c. Carcinoma in situ (general) i. No invasion to stroma, vasculature ii. Ductal carcinoma in situ (DCIS) 1. Most common presentation is mammographic calcification 2. Can have central necrosis 3. Paget’s disease (inflammation, erosion of the nipple) a. Malignant cells travel along collecting ducts to epidermis, unilateral b. Paget’s cells: abundant clear cytoplasm, atypical nuclei w/ prominent nucleoli iii. Lobule carcinoma in situ (LCIS) – much less common, not seen on mammography iv. Tx: local excisions plus irradiation, unless entire portion of breast is involved, then mastectomy d. Invasive Carcinoma i. Invasive ductal carcinoma (much more common) 1. Malignant cells arranged in cords/tubules in background of desmoplasia ii. Invasive lobular carcinoma (not seen on mammogram) 1. No desmoplasia 2. Complete excision NOT indicated b/c does not ↓ future breast cancer risk iii. Inflammatory breast cancer 1. IS NOT INFLAMMATION, it is terminology for the most advanced aggressive stage carcinoma 2. Dermal lymphatic invasion w/malignant cells 3. Skin has orange peel appearance (thick/erythematous/rough) iv. Tx: sentinel lymph node biopsy followed by radiation therapy, if nodes are involved, then node dissection e. Prognostic / Predictive Factors i. Stage 1. Axillary lymph node status – most significant px 2. Tumor size – correlates with Px (˂ 1cm best) 3. Stage 0 – carcinoma in situ or Paget dz of nipple (100% 5 year life-expectancy) a. Tx: Pt can choose between excision/radiation or mastectomy, no need to check lymph nodes 4. Stage 1 – small tumor (˂ 2cm) w/o axillary lymph node involvement a. Tx for invasive breast cancer: first check lymph nodes, radiation to ↓ local recurrence 5. Stage 4 – metastasis (20% 5 year life-expectancy) a. Surgery only for palliation ii. Grade: 1 (well differentiated) – 3 (poorly differentiated) based on tubule formation, pleomorphic nuclei, mitoses iii. Hormonal Receptors: HER-2 Neu positive is worse Px (Hercep test), estrogen R negative is worse Px iv. Gail Model for breast cancer risk: age, age of menarche/first live birth, # family affected, atypia in previous biopsy, race 7. Benign Stromal Tumors a. Fibroadenoma i. Most common stromal tumor ii. Well circumscribed, benign proliferation w/ NO ↑ risk of cancer iii. Reproductive age group (esp. ♀ ˂ 30y) b. Phyllodes tumor: malignant form of fibroadenoma 8. Gynecomastia: in males, only due to ductal proliferation, NOT lobular involvement 9. Recommendations for Breast Maintenance a. Self Breast Exam: start at age 20 b. Clinical exam every 3yrs, then annually at 40 c. Mammogram: annually in women age 40 and older, or 10y prior to when a family member had an early onset breast cancer i. Digital pic better than film for ˂ 50y, dense breasts, pre-menopausal ii. Must biopsy new calcifications in cluster pattern – use stereotactic biopsy d. Breast MRI – is more sensitive but more $, only indicated in pts w/ high lifetime risk (ie BRCA, Cowden (PTEN), Li-Fraumeni (p53)) e. Needle (fine needle, or core biopsy) is the way to go normally f. Non-palpable masses are done by ultra-sound guided stereotactic core biopsy (note that USound doesn’t see Ca) g. Genetic counseling – 1+ close family members affected, male family member affected, Jewish family with hx young dx h. Follow-up for high risk: surveillance, chemoprevention (tamoxifen), prophylactic bilateral simple mastectomy or oophorectemy 10. Tx a. SERM: Tamoxifen blocks estrogen receptor to ↓ growth of breast cancer cells that have ERs b. Aromatase inhibitors (anastrozole, exemestame) – block estrogen formation from androgens, better survival than SERMS c. Trastuzumab (Herceptin) – go after cells over-expressing HER2/NEU d. Bevacizumab (Avastin) – prevents angiogenesis feeding metastatic dz; S/E: delays wound healing, damages kidney, and ↑BP e. ER(–) or HER2/Neu –chemotherapy f. If nodes are involved – chemotherapy g. Chemotherapy combos: i. CMF = cyclophosphamide, MTX, 5-FU ii. CAF = cyclophosphamide, adriamycin/doxorubicin, 5-FU iii. AC = adriamycin/cyclophosphamide (may be followed by taxane) 11. High yield a. Invasive Carcinoma – most common carcinoma presenting as breast mass b. DCIS – highest likelihood to be multicentric ipsilateral disease (remember it follows the milk ducts) c. Lobular carcinoma in situ – highest likelihood to be bilateral d. Phyllodes – often large but mobile e. Inflammatory carcinoma – dermal lymphatic invasion f. Metastases go to: bone ˃ lung ˃ liver ˃ brain g. Breast cancer rarely assoc w/ pregnancy but note that therapeutic abortion does NOT improve maternal survival h. Male breast cancer dx/tx similar to female but no indication for aromatase inhibitors (give SERM) 17 FEMALE PHARM 1. Estrogens (have phenolic A ring) a. E1 = Estrone, 10X less bioactive than E2 b. E2 = 17β-estradiol, most potent and most abundant, made from androstenedione and adrenal DHEA by aromatase c. E3 = Estriol, made in high [ ] by placenta d. DES = potent synthetic that does not bind SHBG and is not rapidly metabolized, can be palliative tx in prostate cancer e. Phytoestrogens (ie genistein) found in soy/clover/hops/flax are weak estrogens f. Must use C17 synthetic derivatives in oral contraceptives to avoid 1st pass effect, avoid SHBG binding, prolong t½ i. Ethinyl Estradiol ii. Mestranol 2. HRT a. Relieves menopausal sx, slows osteoporosis (↓ fractures but doesn’t build bone), but has risks and many DDIs b. Must add progestin to estrogen replacement if uterus is still intact due to risk of endometrial/breast cancer c. Do not start HRT for osteoporosis w/o menopausal sx, the risks (thromboemboli, endometrial/breast cancer) outweigh the benefit d. DDIs: Effects are ↑ by VitC, acetaminophen, protease inhibitors/NNRTIs and ↓ by antibiotics/anticonvulsants 3. PCOS (polycystic ovarian syndrome) a. Lifestyle changes (diet, wt loss, smoking cessation) b. Pharmacotherapy i. Reduce androgenic sx (hirsutism/acne/male pattern baldness) 1. Estrogens/non-androgenic OCPs (norgestimate, desogestrel, drospirenone): ↓LH to ↓ androgen synth, ↑SHBG 2. Antiandrogens: flutamide (R antag), finasteride (5-red inhibitor), glucocorticoids (suppress HPA axis) 3. Eflornithine cream retards hair growth by inhibiting ornithine carboxylase ii. Reduce insulin levels (assume all PCOS pts to have some degree of insulin resistance) 1. Wt loss, which also helps restore ovulation 2. Metformin – ↑ insulin sensitivity, improves ovulation, wt loss, less androgen synth, tx BP/lipids iii. Address fertility 1. Induce ovulation by wt loss, Metformin 2. Beware endometrial hyperplasia (& cancer) risk from chronic anovulation (use combined oral contraceptives) 4. Infertility a. Method is manipulation of FSH/LH via various mechanisms (see chart) DRUG Estrogens MOA PCOS: ↑ E2 fb inhibition ↓ GnRH/LH ↓ androgen production INDICATION ↓ menopause sx + osteoporosis PCOS Progestins PCOS: endometrial protection via withdrawal bleeding Part of HRT if intact uterus PCOS (esp medroxyprogesterone, though no effect on acne/hirsutism/birth control PCOS, hirsutism Infertility Given early in cycle (dy 3-8) Restore menstrual cycle/ovulation Used +/- Clomiphene PCOS, oligomenorrhea Stimulate ovulation Used +/- Clomiphene Stimulate ovulation Used in combo w/ hCG Given during follicular phase Used in combo w/ gonadotropins Given ~day 12-15 Progesterone Norethindrone Medroxyprogesterone Spironolactone Clomiphene (SERM) Metformin AR antag + androgen synth (-) ER antag in HMS ↓ neg fb ↑GnRH/FSH+LH/E2 ovulation Insulin sensitizer (biguanide) ↓ liver glucose synth Thiazolidinediones Rosiglitazone Gonadotropins Insulin sensitizer hCG Elicits LH surge necessary for ovulation Directly ↑FSH levels (exogenous supplementation) SE / CONTRAINDICATION Post-menopausal bleeding, nausea, breast tenderness, HTN, ↑pigment Contra: hx of E2-dependent neoplasm, TE, prego (category X), undx genital bleed, hepatic dz Vaginal bleeding, hyperK Hot flashes Risk of multiple gestations Potential weight gain Risk for multiple gestation OHSS (ovarian hyperstimulation syndrome): excess VGEF ↑capillary permeability ascites/hypovolemia 18 MALE REPRODUCTIVE 1. Normal Physiology a. Pulsatile GnRH stimulates pituitary FSH/LH i. FSH acts on Sertoli cells to enhance spermatogenesis (seminiferous tubules), release is ↓ by inhibin-B (negative fb) ii. LH stimulates Leydig cells to produce testosterone, release is ↓ by testosterone (negative fb) b. Vast majority of testosterone in serum is bound to albumin/SHBG i. Bioactive testosterone = free testosterone ii. Bioavailable testosterone = free testosterone + albumin-bound testosterone (this fraction larger in ♂) c. Testosterone i. DHT via 5-reductase external virilization during embryogenesis + devl’p of male 2˚ characteristics during puberty ii. Estradiol via aromatase bone metabolism effects + gynecomastia 2. Hypogonadism problems in spermatogenesis (infertility & ↓ testicular volume) and/or testosterone production a. Primary: defect in testes i. Klinefelter syndrome (47XXY or 48 XXXY) is most common 1. Damage to seminiferous tubules and Leydig cells no spermatogenesis (infertility) + low testosterone 2. Sx: small/firm testes, eunuchoid proportions (long arms/legs), gynecomastia ( breast cancer) b. Secondary: defect in hypothalamus or pituitary i. Kallmann’s syndrome 1. X-linked KALIG gene mutation isolated GnRH defc’y 2. Sx: anosmia, sx of low testosterone, color blindness/hearing loss can also occur ii. Idiopathic w/ mental retardation: Prader-Willi and Laurence-Moon-Bardet-Biedl iii. Hyperprolactinemia: Elevated PRL suppresses GnRH and FSH/LH 3. Clinical manifestations a. 1st trimester defc’y in primary hypogonadism results in female/ambiguous genitalia + hypospadias b. 1st trimester defc’y in secondary hypogonadism results in micropenis (b/c testosterone production under control of hCG, not LH) c. 3rd trimester defc’y in either results in micropenis d. Pre-pubertal hypogonadism: small/soft testes, small external genitalia, never 2˚ sex characteristics, eunuchoid proportions e. Post-puberty hypogonadism (most common): infertility, regression of 2˚ characteristics, ↓ libido, ED, ↓ muscle mass/↑fat f. Primary is most likely associated with ↓ in sperm production and gynecomastia 4. Dx a. Genital exam, look for: eunuchoid proportions, size of testes, masses in testes, hair distribution, muscle mass, gynecomastia b. Measure testosterone i. Free testosterone is most reliable measure ii. Total testosterone levels drawn in morning and must take into account SHBG levels c. High FSH/LH indicate primary hypogonadism d. High prolactin levels indicate GnRH suppression e. Semen analysis – concentration, motility, morphology (dx abnormality if 3 abnormal samples in 3mo period) i. Normal → 20 million/mL w/ 50% motility 5. Tx a. Testosterone HRT: reverses all the features of impaired sexual characteristics; improves libido/performance, ↑ bone density i. S/E: polycythemia/hyperviscosity syndrome, sleep apnea, acne, gynecomastia, testicular atrophy w/ prolonged tx ii. Contra: known prostate cancer (though does not ↑ risk in those w/o hx), breast cancer, Hct >55% iii. Caution: untx sleep apnea, severe BPH, CHF, Hct ˃50% 19 MALE PATHOLOGY 1. Anatomy of prostate a. Retroperitoneal, surrounds bladder neck/urethra b. Two zones – peripheral zone (prostate cancer) + transition zone (BPH) c. Fibromuscular stroma + secretory glands 2. PSA produced by both benign and malignant epithelium but prostate cancer is dx based on elevated PSA levels a. Higher levels often indicate more advanced tumor b. Levels drop with treatment, rise in re-activation 3. Testicular biopsy determines a. Whether there is an abnormality in spermatogenesis and whether or not it can be corrected i. Endocrine causes: hypogonadism, Klinefelters, testicular aplasia b. Whether there is a germ cell tumor (seminoma vs non-seminoma) or sex cord tumor i. Testicular tumors rare, but most common in young men 15-40, present w/ painless enlarged testis ii. Stages: pTis (in situ), pT1 (epididymis), pT2 (epididymis + vasc/lymph invasion), pT3 (spermatic cord), pT4 (scrotum) 4. Prostate disorders Dz NOTES UTI (E Coli) reflux into gland purulent inflamm w/ PMNs tissue destruction healing w/ fibrosis Acute prostatitis Destruction of epithelium ↑ PSA Chronic prostatitis Sequelea of acute w/ lymphocytes in prostatic secretions, manifests as low back pain Assoc w/ development/conversion to cancer over time Granulomatous prostatitis Idiopathic, TB, iatrogenic Mimics carcinoma on prostate exam ↑ age hyperplasia of transition zone surrounding urethra urethral obstruction dys/poly/noct-uria BPH (aka nodular hyperplasia) Somewhat hormonally driven since anti-androgens alleviate Enlarged gland ↑ PSA Pressure atrophy of peripheral zone Prostatic carcinoma Precursor lesion = PIN (prostatic intraepithelial neoplasia): crowded cells w/ macronucleoli, basophilic ↑ w/ age, race disparity (blacks ˃ whites ˃ asians) Very slow growing – more men die with prostate cancer than from it Dx by PSA, rectal exam, transrectal US-guided tissue biopsy Gleason score: grade 2-10 (add 2 most common scores), 10 being the worst px/poorest glandular differentiation Stage: T1 (incidental), T1c (elevated PSA), T2 (palpable but confined), T3 (invades seminal v), T4 (invades out) 5. Testicular disorders Cryptorchidism Undescended testis due to hormones, mechanical, idiopathic Eventually atrophies – if bilateral, infertility 50x ↑ risk seminoma Acute torsion Emergency due to venous obstruction Inflammation/Infxn Testicular: mumps orchitis (heals w/o infertility), granulomatous (sudden tender mass) Epididymis: gonorrhea (inflamm destroys) Both: malakoplakia, fungal infxn Germ Cell Tumors Staging: pTis (in situ), pT1 (confined to epididymis), pT2 (to lymph/blood/t.vaginalis), pT3 (invades sperm cord) NSGCT (non-seminoma Metastatic (via lymphatics and blood), usually present at stage pT3+, ave age 30y germ cell tumors) Radioresistant but chemosensitive Elevated -fetoprotein Aka mixed GC tumor Seminoma Confined to testis, but can metastasize via lymph nodes, usually present at stage pT2, ave age 40y (most common) Very radiosensitive, excellent Px Smooth, homogenous tumor, usually not assoc w/ elevated serum markers High -fetoprotein and hCG Embryonal Carcinoma More aggressive, worse px, most common in 20-30y age grp Variegated, areas of hemorrhage/necrosis Yolk Sac Tumor Scaller-Duval cells Areas of hemorrhage/necrosis common, reticular pattern, PAS/diastase-resistant hyaline globules (most common in kids) Elevated -fetoprotein Choriocarcinoma Highly malignant, poor px (high propensity for lymph/blood spread) Elevated hCG IGCN (intratubular germ Carcinoma in situ cell neoplasia) Usually seen in aria surrounding invasive tumors or in contralateral testis from invasive tumor Teratoma Contains cells from all 3 germ lines (mature) Prepubertal: diploid DNA, do not metastasize, not assoc w/ IGCN unclassified Postpubertal: hypo-triploid DNA, does metastasize, assoc w/ IGCN unclassified 6. External genitalia disorders Syphilis Warthin-starry stain for spirochete, sharply demarcated chancre (vs chanchroid) Chancroid H.ducreyi, shallow ulcer w/ undermined edges Granuloma Inguinale Calymmatobacterium granulomatis, bipolar Donovan bodies, large histiocytes Multinucleated viral infection painful, ulcerated vesicles Genital Herpes (HSV II) Condyloma Acuminata HPV infection, see koilocytes Molluscum Contagiosum DNA pox virus Bowenoid Papulosis Koilocytes, full-thickness atypia, assoc w/ HPV (btw genital wart and SCC in situ (aka Bowen dz)) Squamous Cell Carcinoma Minority of male cancers Hypo/epispadias infxn, obstruction Congenital 20 MALE PHARM 1. Hypogonadal tx a. ↓ androgens cause: i. ↓ spermatogenesis & fertility (via LH/FSH defc’y) ii. ↓ libido/ED iii. ↓ muscle mass (↓ nitrogen retention), body hair iv. Osteoporosis, anemia v. Depression vi. Gynecomastia b. HRT should reverse all complications caused by low testosterone i. After 1mo: normal testosterone levels, ↑ energy, ↑ libido/sexual fxn’ing, better mood ii. After 3mo: ↑ muscle mass, ↓ body fat iii. After 6mo: ↑ bone mass DRUG 17-OH T esters T enanthate T cypionate T propionate T undecanoate 17- alkylated Methyltestosterone Fluoxymesterone Patch & Gel forms Andro-derm/gel Buccal forms Striant Anabolic Steroids 19-Nortestosterone Oxandrolone Oxymetholone Stanozolol Danazol 2. MOA Replenishes low levels INDICATION Hypogonadism SE / CONTRAINDICATION Given IM (in oil) every few weeks T prop has short t ½ T undec is oral Replenishes low levels Post-pubertal hypogonadism Replenishes low levels, absorbed readily thru skin Replenishes low levels, absorbed readily thru oral mucosa ↑ anabolic effects > sexual Hypogonadism Given orally 1x/d Hepatotoxicity (rarely used now) -cholestatic hepatitis, adenocarcinoma Avoid skin contact w/ women/kids Difficult to titrate dose of patch Weak progestin/androgen activity Suppress ovulation by (-) LH surge endometriosis Hypogonadism Avoids 1st pass metabolism If you desire a cell w/ Bonds + ARod Long term CV risk, atherosclerosis (altered lipid profile), hepatotoxicity, aggressiveness, infertility Excessive androgen tx a. ↑ androgens cause: i. ↓ spermatogenesis & fertility (via fb inhibition of LH/FSH) ii. Acne, esp in women (via androgenic stimulation of sebaceous glands) iii. Virilization in women iv. Premature physis closure in children v. Erythrocytosis vi. Na/water retention (can exacerbate CHF) DRUG GnRH R Agonists Leuprolide Goserelin Triptorelin GnRH R Antag Plenaxis Non-steroid AR antag Flutamide Bicalutamide 5-reductase (-) Finasteride Ketoconazole Spironolactone MOA Downregulates GnRH R INDICATION Prostate cancer (w/ AR antag) Triptorelin is long-acting;being evaluated for paraphilia/sex deviant SE / CONTRINDICATION Initial surge of testosterone before downregulating R Block GnRH R to block LH release Prostate cancer No initial surge of testosterone Blocks action testosterone Prostate cancer (w/ GnRH agonist) Flut: hepatox, gynecomastia, 3x/d dose Bical: low hepatotox, 1x/d dose Blocks testosterone DHT BPH Alopecia Teratogenic (don’t use in women) ↓ libido/sexual dysfunction Antifungal (-) androgen/glucocorticoid synth AR antagonist Female hirsutism Polycystic ovary syndrome (PCOS) 21 GENETICS IN ENDOCRINOLOGY 1. MEN1/2 (multiple endocrine neoplasia type 1/2) 2. FHH (familial hypocalciuric hypercalcemia) 3. PHP (pseudo-hypoparathyroidism) 4. PPHP (pseudo-pseudo-hypoparathyroidism) 5. PDD I/II/III (polyglandular deficiency disorder type I/II/III): all female predominant (suspect w/ premature ovarian failure) 6. MODY (maturity onset diabetes of the young) Disease MEN1 MEN2 Inheritance AutoD AutoD MOA Inactivation of MENIN tumor suppressor gene Activation of RET oncogene FHH PHP1a AutoD AutoD imprinted Inactivation of CaSR Inactivation of Gs gene (if mutant allele maternal) PHP1b AutoD imprinted AutoD imprinted AutoD Inactivation of Gs gene (if mutant allele paternal) PPHP MODY Altered imprinting of Gs gene Results in ↓ renal expression 5 txn factor genes regulating insulin secretion 6th gene is glucokinase (MODY2) Heterozygous → DM Homozygous → incompatible w/ life PHP2 Type of PDD PDD I PDD II PDD III Onset 3-5y Peak ~30y Middle-age Genetics AutoR AIRE mutation Polygenic dominant Unkwn but may be polygenicD Features Hyperparathyroidism, pituitary tumor, pancreatic tumor Medullary thyroid carcinoma, pheochromocytoma MEN2a: also have Hirshsprung dz, upper back pruritis MEN2b: also have tongue/GI neuromas, thick lips/eyelids Benign hyperCa, hyperparathyroidism, no tx needed HypoCa (PTH-resistant), Albright Hereditary Osteodystrophy (moon face, short stature, mental retard) HypoCa (PTH-resistant) only Albright Hereditary Osteodystrophy only MODY3 (HNF1) most commonly affected, then MODY2 Most DM is T2DM (may be 40+ risk alleles) T1DM shows strong assoc w/ HLA 6p21 ↓ phosphaturic response to PTH Effects Adrenal insufficiency, hypoparathyroid, chronic mucocutaneous candidiasis, alopecia, pernicious anemia, celiac dz/malabsorption, thyroid disorders Adrenal insufficiency, T1DM, vitiligo, thyroid disorders Thyroid disorders 22 HIGH YIELD 1. Signet ring tumor 2. Schiller-Duval bodies 3. Hoarseness 4. Meigs Syndome 5. Hobnailing histopathology 6. Pseudomyxoma peritonei 7. Koilocyte 8. Condyloma acuminate 9. When to worry about the peripheral zone? 10. When to worry about transition zone? 11. KALIG gene mutation 12. RET oncogene 13. Anti-thyroglobulin/TPO Ab 14. Anti-TSH Ab 15. Hurthle cells 16. Pre-tibial myxedema & exopthalmos 17. Psammoma bodies 18. Upper flank abdominal bruit 19. Dysphagia, SOB 20. Hyperpigmentation 21. Vitiligo 22. ACTH stimulation test 23. CRH stimulation test 24. Dexamethasone low/high dose testing 25. Plasma ACTH 26. HPV low risk 27. HPV high risk 28. Laron Dwarfs 29. Inability to lactate following delivery 30. Xanthelesmas, xanthomas, arcus corneae 31. Palmar xanthomas 32. Pancreatitis in childhood 33. Galactorrhea 34. Diff Dx for hirsutism 35. Bitemporal hemianopsia 36. Malignant HTN + HA + sweating + palps 37. Salt and pepper chromatin 38. Test for VitD defc’y 39. Test for VitD tox 40. Most common cause hypocalcemia 41. ↓ adiponectin causes 42. Only drug that significantly ↑ HDL 43. Apo-B100 44. Renal insufficiency contraindication for? 45. Opposes insulin 46. SERM used in infertility 47. Contraindications for testosterone HRT 48. Hyperprolactinemia in men 49. Hyperprolactinemia in women 50. Most common testicular cancer Krukenberg tumors (metastatic carcinoma to ovary; stomach origin) Hallmark of yolk sac tumors, look for -fetoprotein Recurrent laryngeal n damage due to thyroid Ovarian fibroma, pleural effusion, ascites Clear cell carcinoma (malignant epithelial tumor assoc with endometriosis) Tumor of appendix that results in ovarian mucinous borderline tumor Hallmark of HPV (HSIL) HPV infection Prostate cancer Cervical cancer Failure of GnRH cell migration Kallmans (anosmia, hypogonadism) Medullary thyroid carcinoma Hashimoto’s Grave’s Hashimotos thyroditis, eosinophilic inclusions Grave’s Papillary thyroid carcinoma Renal vascular hypertension Compression of esophagus/trachea due to enlarged thryoid Adison’s (primary adrenal insufficiency) Assoc with autoimmune diseases, esp Grave’s & Addison’s For hypocortisolism (Addisons) For pituitary hypofunction (Cushings dz vs ectopic ACTH) For hypercortisolism (Cushings) Ectopic (very high), Cushings dz (normal), adrenal tumor (low) 6, 11 16, 18, 31 GH R problem small, pudgy kids Sheehans (post-partum pituitary infarction) FH, heterozygote Type 3 hyperlipoporteinemia/dysbetalipoproteinemia (apoE mutation) LPL defc’y Hyperprolactinemia Cushings, PCOS, 21hydroxylase severe defects, Anabolic steroid usage Mass on optic chiasm, think pituitary adenoma Pheochromocytoma Medullary thyroid carcinoma 25-VitD 1,25-VitD Chronic kidney disease ↑ insulin resistance (adiponectin secreted by visceral adipocytes) Niacin Expressed on VLDL, IDL, LDL (ONLY one on LDL) Metformin, glyburide glucagons, GH, cortisol, catecholamines Clomiphene Prostate cancer, breast cancer, Hct >50% Secondary hypogonadism (neg fb on GnRH low LH/FSH) Amenorrhea, galactorrhea (same MOA as above) Seminoma Hyperadrenals (Exogenous glucocort, Cushings) CNS problems (psychosis) Salt / Water Imbalance, Excessive Salt Retension->Edema, HTN HTN Impaired Glucose Tolerance Immunosuppresion and Osteoporosis Skin Thinning (Purpura, Stria, Echymoses) Weight Gain (moon face, fat pads, buffalo hump) Alopecia, Hursuitism Gluconeogenesis (req aa, proteolysis weakness) Enzyme defect 21 OHase 17 OHase 11β OHase (CYPB1) 11β OHase (CYPB2) Na wasting +/+ HTN + + - Hypoadrenals (Addisons, 21β-hydroxylase) Excessive salt loss, hypoK -> dehydration, Hypotension Hypotension, orthopnea Hyperpigmentation (high ACTH -> high MSH), vitiligo Weight Loss 21hydroxy: precocious puberty, ambiguous female genitalia Electrolyte disturbances weakeness Female Virilization + + + Pure chol ↑ Congenital FH Acquired Hypothyroidism Nephrotic syndrome Ambiguous Male + - Mixed Type III Combined FH Hypothyroidism Nephrotic syndrome Uncontrolled DM Precocious Male + + + Pure TG ↑ LPL defc’y Apo-C2 defc’y EtOH Estrogen Uncontrolled DM